4.8 Article

Co-delivery of luteolin and TGF-β1 plasmids with ROS-responsive virus-inspired nanoparticles for microenvironment regulation and chemo-gene therapy of intervertebral disc degeneration

期刊

NANO RESEARCH
卷 15, 期 9, 页码 8214-8227

出版社

TSINGHUA UNIV PRESS
DOI: 10.1007/s12274-022-4285-7

关键词

intervertebral disc degeneration; poly(beta-amino ester); luteolin; TGF-beta 1; co-delivery

资金

  1. National Natural Science Foundation of China [81271347, 81871473]

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This study developed a co-delivery system of luteolin and TGF-beta 1 gene for the treatment of intervertebral disc degeneration (IDD) using a polymer self-assembly technique. The results showed that this co-delivery system could inhibit inflammation, restore the balance of synthesis and catabolism, and delay the progression of IDD.
Intervertebral disc degeneration (IDD) is closely related to inflammation and imbalance of synthesis/catabolism of extracellular matrix (ECM) in intervertebral disc (IVD). Considering this, luteolin (LUT), a kind of natural flavonoid with good anti-inflammatory effect and TGF-beta 1 (a gene that promotes the regeneration of ECM) plasmid was co-loaded and co-delivered to nucleus pulposus cells (NPCs). Reactive oxygen species (ROS) responsive cationic copolymer, poly(beta-amino ester)-poly(epsilon-caprolactone) (PBC), with high plasmid DNA (pDNA) compression affinity was synthesized. It can self-assemble into nano-sized polyplexes (pDNA@PBC) with virus-inspired structure and function through which it can transfect pDNA into NPCs with very high efficiency and negligible cytotoxicity. LUT was encapsulated in the hydrophobic core of pDNA@PBC. The co-delivery system, LUT-pTGF-beta 1@PBC, could enhance the cellular uptake of NPCs and manifest excellent sustained drug release in IVD. Real time quantitative polymerase chain reaction (RT-qPCR) and Western blot experiments reveal that the co-delivery system could inhibit inflammation in NPCs and restore the balance of anabolism and catabolism in vitro by activating TGF/SMAD3 and inhibiting NF-kappa B/p65. Moreover, LUT-pTGF-beta 1@PBC retards IDD in vivo as detected by radiological and histological methods with good biosafety in rats. LUT-pTGF-beta 1@PBC may be a promising option for the treatment of IDD.

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